1. Field of the Invention
The present invention relates to polyesters useful for facilitating the separation of blood serum or plasma from the cellular portion of blood.
2. Description of the Related Art
The polyesters of the invention are conveniently formulated into a partitioning composition for use in a blood collection vessel in which the blood sample is subjected to centrifugation until the cellular portion and serum or plasma are completely separated. The physical and chemical properties of the partitioning compositions are such that a continuous, integral seal is provided between the separated blood phases, thereby maintaining separation of the phases after centrifugation and simplifying removal of the serum or plasma from the blood collection vessel. The high volume testing of blood components in hospitals and clinics has led to the development of various devices to simplify the collection of blood samples and preparation of the samples for analysis. Typically, whole blood is collected in an evacuated, elongated glass tube that is permanently closed at one end and sealed at the other end by a rubber stopper having a diaphragm which is penetrated by the double-tipped cannula used to draw the patient's blood. After the desired quantity of blood is collected, the collection vessel is subjected to centrifugation to yield two distinct phases comprising the cellular portion of the blood (heavy phase) and the blood serum or plasma (light phase). The light phase is typically removed from the collection vessel, e.g., via pipette or decantation, for testing.
It has been proposed heretofore to provide manufactured, seal-forming members, e.g., resilient pistons, spools, discs and the like, in blood collection vessels to serve as mechanical barriers between the two separated phases. Because of the high cost of manufacturing such devices to the close tolerances required to provide a functional seal, they have been supplanted by fluid sealant compositions. Fluid sealant compositions are formulated to have a specific gravity intermediate the two blood phases sought to be separated, so as to provide a partition at the interface between the cellular and serum phases. Such compositions typically include a polymer base material, one or more additives for adjusting the specific gravity and viscosity of the resultant composition, and optionally, a network former. Representative prior art fluid sealant compositions include: styrerie beads coated with an anti-coagulant (U.S. Pat. No. 3,464,890); silicone fluid having silica dispersed therein (U.S. Pat. No. 3,780,935); a hydrophobic copolyester including a suitable filler, e.g., silica (U.S. Pat. Nos. 4,101,422 and 4,148,764); a liquid alpha-olefindialkylmaleate, together with an aliphatic amine derivative of smectite clay or powdered silica (U.S. Pat. No. 4,310,430); the reaction product of a silicone fluid with a silica filler and a network former (U.S. Pat. No. 4,386,003); a mixture of compatible viscous liquids, e.g., epoxidized vegetable oil and chlorinated polybutene, and a thixotropy-imparting agent, e.g., powdered silica (U.S. Pat. No. 4,534,798); a thixotropic gel comprising a dual resin component including poly-alpha-pinene of lower density combined with chlorinated octadecene of higher density, said gel further comprising a radiation stabilizer, a network stabilizer, a thixotropic agent and a pigment (U.S. Pat. No. 4,994,393); and a gelatinous material admixed with fine resin particles having an average particle size of 0.01 to 2 microns and having an internal crosslinking density of 0.1 to 3 mmol/g (U.S. Pat. No. 5,169,543).
Ideally, a commercially useful blood partitioning composition should maintain uniform physical and chemical properties for extended time periods prior to use, as well as during transportation and processing of blood samples, readily form a stable partition under normal centrifugation conditions and be relatively inert or unreactive toward the substance(s) in the blood whose presence or concentration is to be determined. Inertness to substances sought to be determined is a particular concern when blood collection vessels are used for therapeutic drug monitoring (TDM), which is assuming an increasingly important role. TDM is established through the accumulated experience of clinicians, and consequently reduces the number of patients receiving dosage levels that are either below detection limits or toxic. Administration of drugs under TDM allows one to take into account such factors as drug tolerance developed with passage of time, presence of multiple physical disorders and synergistic or antagonistic interactions with other therapeutic agents. Among the drugs recommended for administration under TDM are those having dangerous toxicity with poorly defined clinical endpoint, steep dose-response curve, narrow therapeutic range considerable inter-individual pharmacokinetics variability or nonlinear pharmacokinetics, as well as those used in long term therapy or in the treatment of life-threatening diseases. By way of example, the evaluation of blood levels of a number of tricyclic antidepressant compounds, such as imipramine or desipramine, in relation to an empirically established therapeutic range is reported to be particularly useful in the treatment of seemingly drug-refractive depression. TDM is likewise used to monitor the dosage of anficonvulsant drugs, such as phenytoin and phenobarbital which are administered in the treatment of epilepsy, antitumor drugs, such as methotrexate, and other more commonly prescribed drugs, including, but not limited to digoxin, lidocaine, pentobarbital and theophylline.
Reports of recent studies on the effect of blood partitioning compositions on drug concentrations in serum and plasma indicate that care must be taken in the selection of polymeric materials which come into contact with the blood samples obtained for drug assay. See, for example, P. Orsulak et al., Therapeutic Drug Monitoring, 6:444-48 (1984) and Y. Bergqvist et al. Clin. Chem., 3:465-66 (1984). The results of these studies show that the blood partitioning compositions provided in blood collection vessels may account for reduced serum or plasma values, as a result of drug absorption by one or more components of the composition. The reported decreases in measured drug concentrations appears to be time-dependent. One report concludes that the observed decreases in drug concentrations may effectively be reduced by minimizing the interval between collection and processing. Another report recommends that blood samples be transported to the laboratory as soon as possible, with processing occurring within 4 hours. A commercially useful blood collection vessel, however, must produce accurate test results, taking into account routine clinical practices in large institutions, where collection, transportation and processing of blood samples may realistically take anywhere from about 1-72 hours.
U.S. Pat. No. 4,148,764 teaches polyesters useful as a barrier material in blood separation assemblies. The polyesters are comprised of the reaction products of essentially stoichiometric quantities of: (1) a dicarboxylic acid component which is comprised of: (a) aliphatic dicarboxylic acid having from 4 to about 12 carbon atoms, (b) a polymeric fatty acid containing 75% by weight or more of a C36 dibasic acid; (2) a diol component which includes a branched-chain aliphatic dihydric alcohol having 3 to 8 carbon atoms, a mixture of these dihydric alcohols, or a mixture containing at least 50% by weight of the branched-chain aliphatic dihydric alcohols and a straight-chain aliphatic dihydric alcohol having 2 to 8 carbon atoms. The equivalents ratio of (a) to (b) ranges from 0.80:0.20 to 0.97:0.03. The polyesters have an average molecular weight of 2,000-10,000, a kinematic viscosity at 210.degree. F. of 2,000-8,000 centistokes, and a density in the range of from 1.015 to 1.060 g/cm.sup.3 at 25.degree. C.
U.S. Pat. No. 5,124,434 discloses polyesters useful in blood partitioning wherein the polyesters comprise at least four components, namely about one mole of a dicarboxylic acid member and one mole of a diol member wherein said acid member is comprised of a first dicarboxylic acid component having from about 5 to about 60 mole percent of an aliphatic dicarboxylic acid having from 13 to about 22 carbon atoms, a second dicarboxylic acid component having from about 35 to about 90 mole percent of an aliphatic dicarboxylic acid having from 4 to about 12 carbon atoms, and a third dicarboxylic acid component having from about 5 to about 25 mole percent of an aliphatic dicarboxylic acid having about 36 carbon atoms, said polyester being in the form of a viscous liquid and having a density at room temperature in the range of 1.01-1.09. However, U.S. '434 does not suggest the use of dimer diol, a 36 carbon atom dihydric alcohol, as a useful diol member. Also, there is no teaching that a polyester useful in functional blood partitioning compositions having reduced affinity for therapeutic agents present in blood such as phenobarbital and imipramine can be prepared from only three ingredients. The ability to make fluid hydrophobic polyesters with precise density control from three rather than four ingredients provides obvious advantages in terms of simplifying the manufacturing process for their preparation. Fewer reactants means there are fewer opportunities for making errors in charging the reactants to the reaction vessel. Production efficiency is also improved due to the relatively high rate of polycondensation observed during the preparation of the polyesters of the instant invention. It has been observed that the dimer diol containing polyesters are lighter in color than the dimer acid containing polyesters taught in U.S. Pat. No. 5,124,434. The dimer diol apparently affords reduced susceptibility to thermal-oxidative darkening under the reaction conditions employed to prepare polyesters. In addition, when looking at batch to batch variability, the use of dimer diol generates polyesters which have a more nearly constant color than exhibited by the dimer acid containing polyesters. The lighter, and more consistent color of the dimer diol polyesters facilitates color matching when those polyesters are employed in silica-polyester-stabilizer functional blood partitioning compositions.
British patent 685,649 discloses a process for the preparation of polyesters made by reacting succinic acid having an open chain hydrocarbon radical containing from 18 to 26 carbon atoms directly joined to at least one of the methylene groups and an organic compound having two esterifiable hydroxyl groups.
U.S. Pat. No. 4,480,087 teaches polyester waxes which contain as the acid member at least 75 mole percent of alkylsuccinic anhydride or alkenylsuccinic anhydride and the acid functional derivatives thereof, and linear aliphatic and cycloaliphatic glycols having from 2 to 12 carbon atoms as the diol member. The remaining acid member may be a C.sub.4 to C.sub.10 dibasic aliphatic acid such as succinic or adipic acid. The patent does not teach polyester compositions incorporating a 36 carbon atom diol member, nor does it contain any suggestion that such polyester compositions are useful as functional blood partitioning compositions having reduced affinity for therapeutic agents present in blood such as phenobarbital and imipramine.
U.S. Pat. No. 5,101,009 relates to copolyester resins which contain as the acid member either terephthalic acid or a dialkyl terephthalate, and contain as the diol member both a dimer diol and at least one glycol having 2 to 8 carbon atoms. The patent does not teach the use of aliphatic diacids as the acid member, nor does it contain any suggestion that such copolyester compositions are useful as functional blood partitioning compositions having reduced affinity for therapeutic agents present in blood such as phenobarbital and imipramine.
U.S. Pat. No. 5,176,956 discloses an improved biomedical appliance having disposed on a skin-contacting, operant portion thereof, a film or layer of a skin compatible, tacky, pressure sensitive polymeric adhesive, the reaction product consisting of at least on fatty acid dimer based or derived component, including dimer diol, and a suitable co-reactant, including dihydric alcohols. The patent does not contain any suggestion that their polyester compositions are useful as functional blood partitioning compositions having reduced affinity for therapeutic agents present in blood such as phenobarbital and imipramine.